The clinical characteristics of the total study cohort, and of the genotype-positive patient subset, by the number of episodes of syncope during follow-up are shown in , respectively. Comparison of ECG parameters showed increasing QTc with increasing number of syncope. Notably, patients who experienced syncope had a very high frequency of beta-blocker usage (≥88%). In addition, the frequency of ICD usage was significantly higher among patients who experienced syncope, but similar among the 4 syncope subgroups (). Among the 738 genotype-positive patients, the LQT1 and LQT2 genotypes comprised the majority (87%) identified LQTS genotypes (). The mean ages at which the first through fourth episodes of syncope occurred were 9, 10, 11, and 12 years (± 6 years for all), respectively, and the majority (>80%) of subsequent events occurred within 5 years of the prior event. The frequency of patients who experienced ≥1 syncopal events was similar between LQTS patients who did- and did not- undergo genetic testing (37% and 42%, respectively).
Clinical and ECG characteristics by the number of syncopal episodes during follow-up
Risk factors for first and recurrent episodes of syncope
Patients with QTc ≥ 500 msec had a significantly higher cumulative probability of experiencing their first syncope as compared to patients with QTc < 500 msec (75% vs. 48%, respectively; p = <0.001) from birth through age 20 years (). However, among patients who experienced a first syncope, the rate of subsequent events was increased among those who had both QTc < 500 msec and those with QTc ≥ 500 msec (74% and 76%, respectively; p = 0.11) at age 20 years (). Similarly, among patients who experienced 2, 3, and 4 syncopal episodes, the risk for subsequent syncope was virtually identical between patients who had narrow or prolonged Qc (not shown). This was supported by the PWP model for recurrent events (), which showed that QTc ≥500 msec was a powerful independent predictor (>2-fold risk increase; p<0.001) of a first syncopal episode; whereas the risk associated with QTc was significantly attenuated when the endpoints of subsequent episodes of syncope were assessed (2nd syncope: HR= 1.29; 3rd syncope: HR = 0.99, 4th syncope: HR = 0.90; interaction p-value < 0.001 for the null hypothesis that all four HR are identical). The results regarding the association between QTc and the risk of first- and recurrent- events were virtually identical when patients with congenital deafness (n=48) and multiple mutations (n=17) were excluded from the analysis. Furthermore, a secondary analysis, in which QTc was categorized at the upper quartile of the study population (≥540 msec [n=425]) or as a continuous measure, consistently demonstrated that QTc was predictive only of a first event and not of subsequent events (not shown).
Probability of cardiac events by QTc
Multivariate Analysis (total population): Predictors of first- and recurrent syncopal events
A gender-genotype specific analysis, that was carried out in a subset of 644 patients having either the LQT1 (n=387) or LQT2 (n=257) genotypes, showed age-dependent risk factors for first- and subsequent syncope ( and ). During childhood, LQT1 males had the highest cumulative probability for a first syncope (36% during 10 years of follow-up ). In contrast, after the occurrence of a first event, the cumulative probability of a subsequent syncopal episode during childhood was increased substantially in all genotype-gender subgroups (35–46% during only 2-years of follow-up ). Consistent with these findings, multivariate analysis showed that during childhood, LQT1 males exhibited a significant increase in the risk of a first syncope (p = 0.001 for the overall difference among the subgroups) but did not show a statistically significant increase in the risk of subsequent events (p = 0.34 for the overall difference among the subgroups).
Cumulative probability of first and second syncope by gender and genotype during childhood
Cumulative probability of first and second syncope by gender and genotype during adolescence
After the onset of adolescence there was an age-gender risk-reversal, and LQT2 females showed the highest rate of both first a syncope (38% during 5-years of follow-up ), and subsequent events (58% during only 2-years of follow-up [). Similarly, multivariate analysis showed that females with the LQT2 genotype in the age-range of 13 through 20 years exhibited a higher risk for both a first- and subsequent events as compared with the other gender-genotype groups (p = 0.001 and p = 0.02, respectively, for the overall difference).
Recurrent syncope and the risk of subsequent aborted cardiac arrest or sudden cardiac death
After adjustment for QTc, gender, and time-dependent beta-blocker therapy, the occurrence of recurring episodes of syncope was associated with a pronounced increase in the risk of subsequent ACA or SCD (). As compared with no events, having 1 or 2 syncopal episodes were associated with >6-fold (p<0.001) increased risk of subsequent ACA or SCD; and having >2 episodes was associated with a >12-fold (p<0.001) relative risk of subsequent fatal or near-fatal events (Table 4). Combined assessment of the number of syncopal episodes and QTc () showed that the 5-year cumulative probability of ACA or SCD was lowest among those who did not experience syncope (1% and 5% in patients with QTc < 500 msec and ≥ 500 msec, respectively); intermediate among those who experienced 1 or 2 syncopal episodes (11–14%); and highest among those who experienced > 2 syncopal episodes 17–21%). Notably, the effect of QTc on the risk of subsequent ACA or SCD was pronounced prior to the occurrence of a first syncope, and attenuated following the occurrence of syncope ().
Multivariate Analysis (Cox Model): Recurrent Syncope as a predictor for ACA/SCD*
5-year cumulative probability of ACA/SCD by the number of syncope and QTc*
Beta-blocker usage was associated independently with a significant and a substantial reduction in the risk of both first and recurrent syncopal episodes (). The magnitude of risk reduction associated with beta-blocker therapy was similar in LQT1 and LQT2 patients. Furthermore, treatment with beta-blockers was associated with a significant >70% reduction in the risk of subsequent fatal or near-fatal events among patients who experienced first- and recurrent- episodes of syncope ().